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Virol Res J 2017 Volume 1 Issue 3
International Virology Conference
October 30-31, 2017 | Toronto, Canada
Enteroviral infection leads to cytoplasmic mislocalization of TDP-43 in mouse brain
Yuan Chao (Tim) Xue1,2, Gabriel Fung1,2, Yasir Mohamud1,2, Haoyu Deng1,2, Huitao Li1,2, Jingchun Zhang 1,2, Ralph Feuer3, Neil Cashman 2 and Honglin Luo1,2
1St. Paul’s Hospital, Canada
2University of British Columbia, Canada
3San Diego State University, USA
Background: Amyotrophic lateral sclerosis (ALS) is a
neurodegenerative disease that targets the motor neurons in
the brain and spinal cord, which control the motor movements
of the body. The disease is present in similar proportions in
the majority of ethnic groups around the world, with the male
being the more likely gender to contract the disease. Currently,
without any effective therapies, the destruction of the motor
neurons will first lead to paralysis, and eventually death. Even
though 5% of all ALS cases have been associated with inherited
genetic mutations that have been categorized as familial ALS,
themajority of all ALS cases are actually sporadic (95%). In other
words, these cases occur in the absence of prior ALS history in
the family. Enterovirus (EV), a family of positive-stranded RNA
viruses including poliovirus and coxsackievirus, is suspected
to influence ALS pathogenesis due to the viruses’ ability to
target motor neurons. In addition, it has also been shown that
patients with prior poliomyelitis, paralysis caused by poliovirus,
are at a higher risk of ALS than those without. Our lab recently
found that in vitro EV infection results in protein aggregation,
RNA-processing defects and disruption of autophagy via EV-
encoded proteases. Of particular interest was the finding that
EV infection is able to impair nucleocytoplasmic trafficking, and
initiate cytoplasmic aggregation and cleavage of transactive
responseDNAbindingprotein-43 (TDP-43), oneof thehallmarks
of ALS. Together with these findings, we hypothesize that EV
infection is a causative and/or risk factor in the development of
sporadic amyotrophic lateral sclerosis.
Methods & Results: Neonatal BALB/C mice were infected
intracranially with eGFP-coxsackievirus or mock (DMEM)
infected. Brain tissues were then collected at 2, 5, 10,
30 and 90 days post-infection for performing H&E and
immunohistochemical staining. Based on our preliminary
data, we were able to show brain lesions and inflammation,
identified using IBA1 (microglia), pSTAT3 (astrogliosis) and GFAP
(reactive astrocytes) in the cortical and hippocampus regions
in parallel with viral protein detection through GFP staining as
early as 2 days post-infection. Even though the viral protein was
significantly decreased to only 10% of the original intensity at
90 days post-infection, there was sustained inflammatory and
immune responses at the later time points. Most notably, our
pilot data demonstrated clear ALS-like pathologies, such as
cytoplasmic mislocalization and nuclear down-regulation of
TDP43 at the areas of infection/tissue damages starting at 5
days post-infection and maintained until 90 days post-infection.
Moreover, localization of markers such as p62 and ubiquitin has
also been strongly detected within the infected regions.
Conclusion: Our preliminary results reveal that enterovirus
infection, such as coxsackievirus, is able to cause ALS-like
pathology, especially in the case of localization in abnormal
TDP-43, p62 and ubiquitin within the virus infected regions of
the mouse brains.
Speaker Biography
Yuan Chao Xue is a PhD student from University of British Columbia, Canada, Centre for
Heart Lung Innovation, St. Paul’s Hospital 2 Department of Pathology and Laboratory
Medicine, University of British Columbia, Canada.
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